Heat shock proteins (HSPs) are a class of chaperone proteins that are up-regulated in response to elevated temperature and other environmental stresses, such as ultraviolet light, nutrient deprivation and oxygen deprivation. HSPs act as chaperones to other cellular proteins (called client proteins), facilitate their proper folding and repair and aid in the refolding of misfolded client proteins. There are several known families of HSPs, each having its own set of client proteins. The Hsp90 family is one of the most abundant HSP families accounting for about 1-2% of proteins in a cell that is not under stress and increasing to about 4-6% in a cell under stress. Inhibition of Hsp90 results in the degradation of its client proteins via the ubiquitin proteasome pathway. Unlike other chaperone proteins, the client proteins of Hsp90 are mostly protein kinases or transcription factors involved in signal transduction, and a number of its client proteins have been shown to be involved in the progression of cancer. Because pharmacological inhibition of Hsp90 destabilizes client proteins, which leads to the degradation of these proteins, tumors are proposed to be more sensitive to the inhibition of Hsp90, as tumors are more dependent on the chaperone activity of Hsp90 than non-malignant cells. Since targeted inhibition of Hsp90 results in the simultaneous blockade of multiple oncogenic signaling pathways, it has emerged as an attractive strategy for the development of novel cancer therapeutics.
In addition to regulating a number of oncogenic client proteins, the Hsp90 molecular chaperone also controls the folding of key signaling molecules required to maintain normal cell function in many organs, including the retina. In human clinical trials, Hsp90 inhibition has been associated with visual disorders including blurred vision, flashes, delayed light/dark accommodation, and photophobia. These adverse effects (toxic effect or toxicological effect) involving injury to the retina may be attributable to photoreceptor degeneration and/or cell death, as previously reported in dogs following repeated doses of Hsp90 inhibitor PF-04929113 (a/k/a SNX-5422).